1. Field of the Invention
The present invention relates to methods for treatment of supraventricular tachycardia and other arrhythmias caused by re-entry in the A-V node.
2. Description of the Prior Art
In the mammalian heart the electrical component of each heart beat originates in the sinoatrial node (pacemaker) of the heart and must pass through the atrioventricular (A-V) node in order to reach the ventricles and elicit the contraction needed to pump blood. The electrical components of a heart beat can be detected by an electrocardiogram (EKG) and appear as follows: first, an electrical impulse known as P-wave, which indicates the triggering of the sinoatrial node and activation of the atria, and second, a complex group of electrical impluses individually named Q-, R-, S-, and T-waves and collectively known as the ventricular complex, which indicates that the signal has passed the A-V node and that the ventricles are activated to contract. The Q-wave is sometimes quite small and may not be visible; therefore, the interval between atrial and ventricular depolarization (activation) is generally measured by the P-R interval. An EKG of a normal heart is shown in FIG. 1. Normally, both the interval between two P-waves (the time of a complete heart beat) and the interval between a P-wave and following R-wave are consistent from one heart beat to another. The normal P-R interval is about 0.2 second.
Various disfunctions of the heart lead to altered beating. One such alteration is heart block, which occurs when the transmission of a signal through the A-V node is impaired. Heart block leads initially to a slowing of heart beat and can progress to such a degree that beats are missed entirely or even that the atria and ventricles beat independently. Conversely, other conditions may lead to more rapid heart beat, for example, arrhythmias caused by re-entry in the A-V node. Conditions of excessively rapid heart beat are known as tachycardia. When tachycardia is caused by rapid discharges from an abnormal atrial pacemaker, it is known as paroxysmal atrial tachycardia or more recently by the name paroxysmal supraventricular tachycardia. Recent evidence suggests that many instances of paroxysmal supraventricular tachycardia are symptoms of reciprocating rhythms resulting from a short-circuit in which electrical impulses pass back through the A-V node, or more likely through an accessory pathway (e.g., Wolf-Parkinson-White, preexcitation syndrome), and initiate new beats before they would normally occur. Tachycardia usually appears in youth and often reoccurs throughout adult life, notably in individuals with preexcitation syndrome. Although paroxysmal atrial tachycardia is generally benign, the attack may ocassionally bring on congestive failure or myocardial ischemia.
Considerable information is known regarding conditions of the heart which affect A-V node transmission. These conditions include ischemia (lower blood flow to heart tissue) and hypoxia (low oxygen blood level) of the A-V node. Furthermore, it was known that A-V node action potentials (electrical potential during activity of the node) are depressed by hypoxia and, concomitantly, the atria-to-His bundle conduction time is markedly increased. The His bundle is a small bundle of atypical cardiac muscle fibers that propagates the electrical signal from the atrial to the ventricular end of the A-V node. Additionally, stimulation of the vagus nerve, the parasympathetic nerve that controls heart beat, results in slowing the heart beat and an increase in the P-R interval. The vagus nerve interacts with the heart by releasing acetylcholine, and, therefore, the presence of high levels of acetylcholine will also cause A-V conduction disturbances. Lastly, as early as 1929 it was observed that adenosine, if injected in large amounts, can produce heart block. Adenosine is normally present in myocardial tissue, as well as in other tissues, but is normally present only in much lower concentrations than those that produce heart block. Adenosine and adenine nucleotides have been shown to produce dose-dependent A-V conduction block in guinea pig hearts. Adenosine is also known to depress Ca.sup.2+ -mediated action potentials in mammalian atria.
Presently, A-V node block and specific types of tachycardia can be determined with certainty only from an electrocardiogram (EKG). If an EKG is not available, clinical techniques of heart beat monitoring by stethoscope or by taking of the pulse may give some indication of these disorders, but with considerable less certainty.
Supraventricular tachycardia is typically treated by the avoidance of factors, such as anxiety, digestive disturbances, or hyploglycemic episodes, where these factors are known to trigger episodes. Various drugs, such as digitalis and verapamil, also effective. The use of adenosine triphosphate (ATP) in order to stop paroxysmal supraventricular tachycardias and to facilitate the diagnosis of atrial tachycardia (flutter and fibrillation) by the transient A-V node block produced by this drug was introduced in 1955 [Komor et al, Lancet, 269, 93 (1955); Somlo, Lancet, 268, 1125 (1955)]. ATP was thought by its users to slow the ventricle through an independent effect that did not depend on the formation of adenosine. ATP was typically administered at a dosage rate of 30 mg. Although this dose does not usually cause major problems, a reduction in the amount of medication used is desirable, as it would be for all medications.